Drug Metabolism in Early Stage Drug Discovery and Drug Development
thesisposted on 20.06.2014, 00:00 authored by Nan Zhang
Drug metabolism is an essential element in drug discovery and development process by interacting with multiple disciplines, including medicinal chemistry, pharmacology, preclinical development, clinical development, safety assessment and regulatory affairs. Although the methodologies in this area have been being developed and applied for decades, improvement of the efficiency of the method in drug discovery program is still needed. In this thesis, a novel in vitro method to detect the liver enzymes derived active metabolites against Mycobacterial tuberculosis was developed. As the primary pathway of the drug clearance, hepatic metabolism changes the active form of the drug into a more polar structure for the further elimination. This metabolism has also been utilized to design pro-drug which is not active but can be converted to the active form through this process. This in vitro assay will identify the TB-active metabolites which have better metabolic, pharmacokinetic and safety profiles. Besides, the drug-drug interactions was explored with four commonly used tyrosine kinease inhibitors, including axitinib, imatinib, lapatinib and vandetinib in terms of their inhibition of the glucuronidation activities of UGT enzymes. The coadministered drugs which are cleared through glucuronidation will be affected with increased AUC and may cause adverse effects. The mechanism of drug-drug interactions between (S)-warfarin and noscapine was also investigated. It was found that the inhibition of 7-hydroxylation of (S)-warfarin occurs through mechanism-based inactivation. The methylenedioxyphenyl structure of noscapine is oxidized by CYP2C9 to form the active species carbene, which then chelates to the heme of CYP2C9 and inactives its activity. This inactivation activity of noscapine was also studied in CYP2C9 variant isoforms, including CYP2C9*1, *2, and *3. With the amino acid mutations, the inactivation differs in these isoforms, which affected the clearance of (S)-warfarin at different levels. Due to the effects on the clearance of (S)-warfarin, the dose adjustment factor of (S)-warfarin for different CYP2C9 variant carriers was calculated in order to avoid the adverse effects of bleeding.